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TRIMETHOPRIM

Category Antibacterial. 

      Trimethoprim contains not less than 98.5 per cent and not more than 101.0 per cent of C14H18N4O3, calculated on the dried basis.

Description White to cream-coloured crystals or crystalline powder.

Solubility Very slightly soluble in water; soluble in benzyl alcohol; sparingly soluble in chloroform and in methanol; slightly soluble in ethanol and in acetone; practically insoluble in ether and in carbon tetrachloride.

Contra-indication It is contra-indicated in patients with megaloblastic anemia secondary to folate deficiency.

Warning

      1. It should be used with caution in patients with impaired renal or hepatic function or with possible folate deficiency and in children or pregnant women who are at risk of having a child with the fragile X chromosomes associated with mental retardation.

      2. It may cause rash, pruritus, photosensitivity, exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson Syndrome, nausea, vomiting, glossitis, abnormal taste sensation, elevation in serum aspartate transaminase (AST), serum alanine transaminase (ALT) and bilirubin levels, cholestatic jaundice and blood dyscrasias.

      3. Risk-benefit should be considered if it is to be used in children, pregnant or nursing women.

      4. Caution should be exercised if it is to be used concomitantly with other folate antagonists.

Precaution Monitoring and early signs and symptoms of a serious hematologic disorder, including fever, sore throat, pallor, or purpura are recommended. Periodic blood counts including platelet counts are recommended during therapy with the drug. If signs of folic or folinic acid deficiency develop, reduce the dosage or discontinue the drug according to the response of the patient. Folinic acid at a dose of 3 to 10 mg per day intramuscularly should be given until the blood picture returns to safe levels.

Additional information Safety and efficacy of trimethoprim in infants younger than 2 months of age and efficacy of the drug when used as a single agent in children younger than 12 years of age have not been established.

Packaging and storage Trimethoprim shall be kept in well-closed containers.

Identification

      A. The infrared absorption spectrum is concordant with the spectrum obtained from Trimethoprim RS (Appendix 2.1) or with the reference spectrum of Trimethoprim.

      B. The ultraviolet absorption spectrum of a 0.002 per cent w/v solution in 0.1 M sodium hydroxide, when observed between 230 and 350 nm, exhibits a maximum only at 287 nm; the absorbance of a 1-cm layer at this wavelength is about 0.49 (Appendix 2.2).

      C. Dissolve, with heating if necessary, 25 mg in 5 ml of 0.005 M sulfuric acid and add 2 ml of a 1.6 per cent w/ v solution of potassium permanganate in 0.1 M sodium hydroxide. Heat to boiling and add to the hot solution 8 drops of formaldehyde solution. Mix, add 1 ml of 0.5 M sulfuric acid, mix and again heat to boiling. Cool to room temperature and filter. Add to the filtrate 2 ml of chloroform and shake vigorously: the chloroform layer exhibits a green fluorescence when examined under ultraviolet light (366 nm).

Melting range 199º to 203º (Appendix 4.3).

Loss on drying Not more than 1.0 per cent w/w after drying at 105º to constant weight (Appendix 4.15).

Sulfated ash Not more than 0.1 per cent w/w (Appendix 5.3).

Chromatographic purity Not more than 0.1 per cent w/w of any individual impurity; and not more than 0.2 per cent w/w of total impurities. Carry out the determination as described in the “High-pressure Liquid Chromatography” (Appendix 3.5).

      Buffer solution Prepare a 0.01 M sodium perchlorate solution in water, adjust with phosphoric acid to a pH of 3.6, and mix.

      Mobile phase Prepare a mixture of 7 volumes of Buffer solution and 3 volumes of methanol. Make adjustments if necessary.

      Resolution solution Dissolve accurately weighed quantities of Trimethoprim RS and diaveridine, and dilute quantitatively, and stepwise if necessary, with Mobile phase to obtain a solution having known concentrations of about 10 μg per ml and 5 μg per ml, respectively.

      Test solution Transfer about 25.0 mg of the test substance, accurately weighed, to a 25-ml volumetric flask, dissolve in and dilute with Mobile phase to volume, and mix.

      Chromatographic system The chromatographic procedure may be carried out using (a) a stainless steel column (25 cm × 4.6 mm) packed with octadecylsilane chemically bonded to porous silica or ceramic microparticles (3 to 10 μm in diameter), (b) Mobile phase at a flow rate of 1.3 ml per minute, and (c) an ultraviolet photometer set at 280 nm.

      To determine the suitability of the chromatographic system, chromatograph Resolution solution, and record the peak responses as directed under Procedure: the resolution factor between the peaks for trimethoprim and diaveridine is not less than 2.5; and the relative standard deviation for replicate injections is not more than 2.0 per cent.

      Procedure Inject a volume (about 20 μl) of Test solution into the chromatograph, record the chromatogram for not less than 11 times the retention time of the trimethoprim peak, and measure all of the peak responses.

      Calculation Calculate the percentage of each impurity in the portion of Trimethoprim taken by the expression:

100[Fri/[∑(Fri ) + Frt ]] ,

in which F is a relative response factor, and is equal to 0.5 for any peak having a relative retention time of 0.9, 2.3, 2.7, or 10.3, and is equal to 1.0 for all other peaks; ri is the peak response for each impurity; and rt is the peak response for trimethoprim obtained from Test solution.

Assay Dissolve about 300 mg of Trimethoprim, accurately weighed, in 60 ml of anhydrous glacial acetic acid and titrate with 0.1 M perchloric acid VS, using crystal violet TS as indicator, to a blue-green end-point, or determining the end-point potentiometrically (Appendix 6.1). Perform a blank determination, and make any necessary correction. Each ml of 0.1 M perchloric acid is equivalent to 29.03 mg of C14H18N4O3.

MONOGRAPHS • TRIMETHOPRIM
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หมายเหตุ / Note : TP II 2011 PAGE 166 - 167